1. Field of the Invention
This invention is directed to novel compounds, which are useful as inhibitors of matrix metaloproteinases in treating diseases associated with these enzymes.
2. Description of the Related Art
Matrix metaloproteinases (MMPs) are a superfamily of proteinases whose numbers have increased dramatically in recent years. They are believed to be important in the uncontrolled breakdown of connective tissue, which relates to a few disease processes such as rheumatoid arthritis, osteoarthritis, gastric ulceration, asthma, emphysema, and tumor metastasis. Therefore, inhibition of one or more MMPs may be of benefit in these diseases.
Human macrophage elastase (MMP-12) exhibits all the characteristics of other MMPs, but is preferentially produced from macrophages infiltrating into tissues where injury or remodeling is occurring and degrades extracellular matrix. The demonstration of the increase of the level of MMP-12 during the manifestation of emphysema suggests that a crucial role of this enzyme. Likewise, MMP-12 knocked out mouse model also demonstrated no development of emphysema by being exposed for a lengthy period of time to cigarette smoke (Science, 1997, 277: 2002–2004). More recently, using MMP-12 deficient model of asthma, the investigator suggested the involvement of MMP-12 in the development of chronic asthma (FASEB, 2002, 16: A590). These results imply that inhibitors of MMP-12 might be very useful in the treatment of pulmonary diseases, such as chronic obstructive pulmonary disease (COPD), emphysema and asthma.
MMP-12 has been shown to be secreted from alveolar macrophages of smokers (Shapiro et al, 1993, Journal of Biological Chemistry, 268: 23824), in foam cells in atherosclerotic lesions (Matsumoto et al, 1998, Am J Pathol 153: 109), and in nephritis rat model (Yoshikatsu Kaneko et al, 2003 J Immuol 170:3377). It was also showed that MMP-12 plays a role in coronary artery disease (Sofia Jormsjo et al, 2000, Circulation Research, 86: 998). These observations suggested that MMP-12 could be the targets of these disease treatments.
In view of the involvement of MMP-12 in a number of diseases, attempts have been made to prepare its inhibitors. A number of MMP-12 inhibitors are known (see e.g., published PCT Patent Application No. WO 00/40577; EP 1 288 199 A1, 2001, Shionogi & Co. MMP-12 Inhibitor; U.S. Pat. No. 6,352,9761, and U.S. Patent Application Publication No. 2004/0072871; published European Patent Application EP1394159). Lately, there is a new class of MMP inhibitors disclosed in this field. A published PCT Patent Application No. WO 02/096426 describes hydantoin derivatives of formula
where the substitutents R1, R2, R3, R4, R5, R6, R7, and R11 are widely defined. The derivatives are active as MMP inhibitors, in particular for TACE and aggrecanase, although there were no biological data demonstrated. The feature of the structures of these derivatives is the spiro-linkage between the hydantoin ring and its side chain.
U.S. Patent Application Publication No. 2004/0067996 and published PCT Patent Application No. WO 2004/108086 describe similar hydantoin derivatives of formula
where R1, R4, R5, and R11 were also broadly defined. The derivatives in these two patents are also said, in general term, to be inhibitors of metalloproteinase and in particular for TACE and aggrecanase. Still, there were no biological data demonstrated.
Published PCT Patent Application No. WO 02/074752 describes the synthesis of hydantoin derivatives as matrix metalloproteinase inhibitors. These are the first series of hydantoin derivatives as MMP inhibitors with general structure of
where Y1, Y2, R6, B, and G are well defined. It was generally said that these compounds showed MMP inhibitory activities and some of them have been discovered to be potent MMP-12 inhibitors, but there were no biological data provided in detail.
Another published PCT Patent Application No. WO 2004/020415 discloses a group of MMP-12 inhibitors of formula
where R1, R2, R3, X, Y, Z1, Z2, L, and G are well defined. IC50 values of some compounds are provided, but lacking the selectivity data in detail.
Hydantoin derivatives are a new class of MMP inhibitors. It is desirable to find more new compound of this class with improved specificity, potency, and pharmacological characteristics.